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WO2003003013A1 - Effets non nucleaires d'hormone thyroidienne - Google Patents

Effets non nucleaires d'hormone thyroidienne Download PDF

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Publication number
WO2003003013A1
WO2003003013A1 PCT/US2001/020879 US0120879W WO03003013A1 WO 2003003013 A1 WO2003003013 A1 WO 2003003013A1 US 0120879 W US0120879 W US 0120879W WO 03003013 A1 WO03003013 A1 WO 03003013A1
Authority
WO
WIPO (PCT)
Prior art keywords
δtrα2
animal
test compound
gene
cell
Prior art date
Application number
PCT/US2001/020879
Other languages
English (en)
Inventor
Jack L. Leonard
Alan P. Farwell
Original Assignee
University Of Massachusetts
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University Of Massachusetts filed Critical University Of Massachusetts
Priority to PCT/US2001/020879 priority Critical patent/WO2003003013A1/fr
Publication of WO2003003013A1 publication Critical patent/WO2003003013A1/fr

Links

Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
    • G01N33/78—Thyroid gland hormones, e.g. T3, T4, TBH, TBG or their receptors
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
    • A01K67/027—New or modified breeds of vertebrates
    • A01K67/0275—Genetically modified vertebrates, e.g. transgenic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/72—Receptors; Cell surface antigens; Cell surface determinants for hormones
    • C07K14/721—Steroid/thyroid hormone superfamily, e.g. GR, EcR, androgen receptor, oestrogen receptor
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/8509—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells for producing genetically modified animals, e.g. transgenic
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/07—Animals genetically altered by homologous recombination
    • A01K2217/072—Animals genetically altered by homologous recombination maintaining or altering function, i.e. knock in
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/07—Animals genetically altered by homologous recombination
    • A01K2217/075—Animals genetically altered by homologous recombination inducing loss of function, i.e. knock out
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2227/00—Animals characterised by species
    • A01K2227/10—Mammal
    • A01K2227/105—Murine
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/03—Animal model, e.g. for test or diseases
    • A01K2267/035—Animal model for multifactorial diseases
    • A01K2267/0356—Animal model for processes and diseases of the central nervous system, e.g. stress, learning, schizophrenia, pain, epilepsy
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2800/00—Nucleic acids vectors
    • C12N2800/30—Vector systems comprising sequences for excision in presence of a recombinase, e.g. loxP or FRT
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value

Definitions

  • the invention provides a method of identifying a candidate compound that modulates ⁇ TR ⁇ 2 activity.
  • This method includes obtaining a ⁇ TR ⁇ 2 polypeptide bound to a ⁇ TR ⁇ 2 ligand, contacting the ⁇ TR ⁇ 2 bound to the ⁇ TR ⁇ 2 ligand with a test compound, and measuring the displacement of the ⁇ TR ⁇ 2 ligand from the ⁇ TR ⁇ 2 polypeptide, such that displacement indicates that the a test compound is a candidate compound that modulates ⁇ TR ⁇ 2 activity.
  • the test compound can be, e.g., a flavone, an aurone, or a T4 analog.
  • the invention also includes a method of identifying a candidate compound that modulates ⁇ TR ⁇ 2 activity.
  • a " ⁇ TR ⁇ l ligand” or “ ⁇ TR ⁇ 2 ligand” is a compound that binds to a ⁇ TR l or ⁇ TR ⁇ 2, respectively. In some embodiments such a ligand binds to a ⁇ TR ⁇ l or ⁇ TR ⁇ 2 with an affinity of greater than or equal to 10 "8 Mol/L.
  • a molecule that "specifically binds" is a molecule that binds to a particular entity, e.g., a ⁇ TR ⁇ l or ⁇ TR ⁇ 2, but which does not substantially recognize or bind to other molecules in a sample, e.g., a biological sample, which includes that particular entity, e.g., a ⁇ TR ⁇ l or ⁇ TR ⁇ 2.
  • Gapped BLAST can be utilized as described in Altschul et al., (1997) Nucleic Acids Res. 25:3389-3402.
  • the default parameters of the respective programs e.g., XBLAST and NBLAST
  • the default parameters of the respective programs e.g., XBLAST and NBLAST

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Organic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Zoology (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Endocrinology (AREA)
  • Immunology (AREA)
  • Veterinary Medicine (AREA)
  • Hematology (AREA)
  • Wood Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • Physics & Mathematics (AREA)
  • Environmental Sciences (AREA)
  • Urology & Nephrology (AREA)
  • Cell Biology (AREA)
  • Biophysics (AREA)
  • Microbiology (AREA)
  • Pathology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Animal Husbandry (AREA)
  • Biodiversity & Conservation Biology (AREA)
  • Toxicology (AREA)
  • General Physics & Mathematics (AREA)
  • Plant Pathology (AREA)
  • Food Science & Technology (AREA)
  • Analytical Chemistry (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

On a découvert que les récepteurs d'hormone thyroïdienne tronqués δTRα1 et δTRα2 jouaient un rôle dans l'endocytose à base d'actine, par exemple dans le système nerveux. Cette invention concerne des techniques permettant de découvrir des ligands efficaces pour moduler l'endocytose et des souris transgéniques dont l'expression de δTRα1 et de δTRα2 a été modifiée. Cette invention convient pour découvrir et tester des composés destinés à traiter des troubles du système nerveux tels que la dépression.
PCT/US2001/020879 2001-06-29 2001-06-29 Effets non nucleaires d'hormone thyroidienne WO2003003013A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/US2001/020879 WO2003003013A1 (fr) 2001-06-29 2001-06-29 Effets non nucleaires d'hormone thyroidienne

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2001/020879 WO2003003013A1 (fr) 2001-06-29 2001-06-29 Effets non nucleaires d'hormone thyroidienne

Publications (1)

Publication Number Publication Date
WO2003003013A1 true WO2003003013A1 (fr) 2003-01-09

Family

ID=21742676

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2001/020879 WO2003003013A1 (fr) 2001-06-29 2001-06-29 Effets non nucleaires d'hormone thyroidienne

Country Status (1)

Country Link
WO (1) WO2003003013A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7514419B2 (en) 2003-11-19 2009-04-07 Metabasis Therapeutics, Inc. Phosphorus-containing thyromimetics
US10130643B2 (en) 2005-05-26 2018-11-20 Metabasis Therapeutics, Inc. Thyromimetics for the treatment of fatty liver diseases
US11202789B2 (en) 2016-11-21 2021-12-21 Viking Therapeutics, Inc. Method of treating glycogen storage disease
US11707472B2 (en) 2017-06-05 2023-07-25 Viking Therapeutics, Inc. Compositions for the treatment of fibrosis
US11787828B2 (en) 2018-03-22 2023-10-17 Viking Therapeutics, Inc. Crystalline forms and methods of producing crystalline forms of a compound
US12102646B2 (en) 2018-12-05 2024-10-01 Viking Therapeutics, Inc. Compositions for the treatment of fibrosis and inflammation

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5650550A (en) * 1993-10-01 1997-07-22 The United States Of America As Represented By The Department Of Health And Human Services Mutant mice having a deficit of functional estrogen receptors

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5650550A (en) * 1993-10-01 1997-07-22 The United States Of America As Represented By The Department Of Health And Human Services Mutant mice having a deficit of functional estrogen receptors

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BURRIS ET AL.: "A nuclear hormone receptor-associated protein that inhibits transactivation by the thyroid hormone and retinoic acid receptors", PROC. NATL. ACAD. SCI. USA, vol. 92, October 1995 (1995-10-01), pages 9525 - 9529, XP002943268 *
CHASSANDE ET AL.: "Identification of transcripts initiated from an internal promoter in the c-erbalpha locus that encode inhibitors of retinoic acid receptor-alpha and triiodothyronine receptor activities", MOLECULAR ENDOCRINOLOGY, vol. 11, no. 9, 1997, pages 1278 - 1290, XP002906700 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7514419B2 (en) 2003-11-19 2009-04-07 Metabasis Therapeutics, Inc. Phosphorus-containing thyromimetics
US7829552B2 (en) 2003-11-19 2010-11-09 Metabasis Therapeutics, Inc. Phosphorus-containing thyromimetics
US10130643B2 (en) 2005-05-26 2018-11-20 Metabasis Therapeutics, Inc. Thyromimetics for the treatment of fatty liver diseases
US10925885B2 (en) 2005-05-26 2021-02-23 Metabasis Therapeutics, Inc. Thyromimetics for the treatment of fatty liver diseases
US11202789B2 (en) 2016-11-21 2021-12-21 Viking Therapeutics, Inc. Method of treating glycogen storage disease
US11707472B2 (en) 2017-06-05 2023-07-25 Viking Therapeutics, Inc. Compositions for the treatment of fibrosis
US11787828B2 (en) 2018-03-22 2023-10-17 Viking Therapeutics, Inc. Crystalline forms and methods of producing crystalline forms of a compound
US12227533B2 (en) 2018-03-22 2025-02-18 Viking Therapeutics, Inc. Crystalline forms and methods of producing crystalline forms of a compound
US12102646B2 (en) 2018-12-05 2024-10-01 Viking Therapeutics, Inc. Compositions for the treatment of fibrosis and inflammation

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